Benzoxazole-based Zn(II) and Cu(II) Complexes Overcome Multidrug-resistance in Cancer
Benzoxazole-based Zn(II) and Cu(II) Complexes Overcome Multidrug-resistance in Cancer
复制标题
基于苯并恶唑的锌(II)和铜(II)配合物克服癌症的多重耐药性
DOI：
10.21873/anticanres.12971
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发表时间：
2018-11-01
影响因子：
2
通讯作者：
Kawase, Masami
中科院分区：
文献类型：
--
作者：
Spengler, Gabriella;Kincses, Annamaria;Kawase, Masami
背景/目的：多药耐药（MDR）是成功治疗癌症的重要障碍。在这项研究中，新的金属[Zn（II），Cu（II），Mg（II），Ni（II），Pd（II），和Ag（I）]配合物的2-三氟丙酮基-苯并恶唑先前合成和表征，并在L5178 Y小鼠T-淋巴瘤（MDR）细胞中与人ATP结合盒亚家族B成员1转染的游离配体进行比较，测试其MDR逆转活性（ABCB 1; P-糖蛋白）基因。材料与方法：采用噻唑蓝四唑溴化盐（MTT）法测定配合物的细胞毒性和抗增殖作用。ABCB 1活性的调节通过使用流式细胞术的罗丹明123积累测定来测量。还使用膜联蛋白-V/碘化丙啶测定在多药耐药L5178 Y小鼠T淋巴瘤细胞上测试了一些复合物的凋亡诱导活性。结果如下：当与游离配体相比时，发现Zn（II）和Cu（II）络合物在MDR逆转和细胞毒活性中显著增强。证明复合物的活性分别比配体和ABCB 1抑制剂维拉帕米作为阳性对照的活性高29倍和5倍。配合物具有明显的诱导MDR细胞凋亡的潜力。结论：我们的研究结果表明，锌（II）和铜（II）配合物显示出显着的MDR逆转活性在一个剂量依赖性的方式，并具有较强的细胞毒活性和显着的潜力，诱导MDR L5178 Y小鼠T淋巴瘤细胞凋亡。
Background/Aim: Multidrug resistance (MDR) represents a significant impediment to successful cancer treatment. In this study, novel metal [Zn(II), Cu(II), Mg(II), Ni(II), Pd(II), and Ag(I)] complexes of 2-trifluoroacetonyl-benzoxazole previously synthesized and characterized by our group were tested for their MDR-reversing activity in comparison with the free ligands in L5178Y mouse T-lymphoma (MDR) cells transfected with human ATP-binding cassette sub family B member 1 (ABCB1; P-glycoprotein) gene. Materials and Methods: Cytotoxic and antiproliferative effects of the complexes were assessed by the thiazolyl blue tetrazolium bromide (MTT) method. Modulation of ABCB1 activity was measured by rhodamine 123 accumulation assay using flow cytometry. The apoptosis-inducing activity of some complexes was also tested on the multidrug resistant L5178Y mouse T-lymphoma cells, using the annexin-V/propidium iodide assay. Results: When compared to the free ligand, a remarkable enhancement in MDR reversal and cytotoxic activity was found for the Zn(II) and Cu(II) complexes. The activity of the complexes proved to be up to 29- and 5-fold higher than that of the ligands and the ABCB1 inhibitor verapamil as positive control, respectively. The complexes possessed a remarkable potential to induce apoptosis of MDR cells. Conclusion: Our results suggest that the Zn(II) and Cu(II) complexes display significant MDR-reversing activity in a dose-dependent manner and possess strong cytotoxic activity and a remarkable potential to induce apoptosis in MDR L5178Y mouse T-lymphoma cells.